title: Cytotoxicity and antiproliferative effect of hypericin and derivatives after photosensitization.
abstract: The toxicity on three human tumor cell lines (A431, HeLa and MCF7) of five phenanthroperylenequinones (hypericin and derivatives) and two perylenequinones (cercosporin and calphostin C) was investigated after photosensitization (4 J/cm2). Furthermore, the antiproliferative effect on HeLa cells was studied for the phenanthroperylenequinones. Hypericin, 2,5-dibromohypericin, 2,5,9,12-tetrabromohypericin and perylenequinones displayed a potent cytotoxic and antiproliferative effect in the nanomolar range. Hypericin dicarboxylic acid exhibited no photoactivity. In general, the antiproliferative activity correlated well with the photocytotoxicity. However, the nonphotocytotoxic compound hexamethylhypericin showed potent antiproliferative activity in the nanomolar range, probably exerting its action by protein kinase C inhibition. Without light irradiation, no cytotoxic and antiproliferative effect was observed for any photocytotoxic phenanthroperylenequinone compound. Furthermore, confocal laser microscopy revealed that the subcellular localization in A431 cells was similar for the photoactive compounds; the photosensitizers were mainly concentrated in the perinuclear region, probably corresponding with the Golgi apparatus and the endoplasmic reticulum. In addition, the accumulation of the photosensitizers in HeLa cells was investigated. All compounds except hypericin dicarboxylic acid were found to concentrate to a large extent in the cells. The compound 2,5,9,12-tetrabromohypericin seemed intrinsically more effective than hypericin since the intracellular concentration of the bromoderivative was a magnitude of order lower than that of hypericin although both compounds showed similar photobiological activity.
authors.affiliation: Laboratorium voor Farmaceutische Biologie en Fytofarmacologie, Faculteit Farmaceutische Wetenschappen, Katholieke Universiteit Leuven, Belgium.
authors.forename: A L
authors.initials: AL
authors.lastname: Vandenbogaerde
authors.forename: E M
authors.initials: EM
authors.lastname: Delaey
authors.forename: A M
authors.initials: AM
authors.lastname: Vantieghem
authors.forename: B E
authors.initials: BE
authors.lastname: Himpens
authors.forename: W J
authors.initials: WJ
authors.lastname: Merlevede
authors.forename: P A
authors.initials: PA
authors.lastname: de Witte
mesh_terms: D000873:Anthracenes; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D018613:Microscopy, Confocal; D010569:Perylene / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010777:Photochemistry; D011838:Radiation-Sensitizing Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000873:Anthracenes; D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D010569:Perylene; C004965:hypericin